Radiation has long been known to damage biological tissues and cells. Initial deposition of energy in irradiated cells occurs in the form of ionized and excited atoms or molecules distributed at random throughout the cells. The ionizations cause chemical changes in the exposed area, producing highly unstable charged or “ionized” molecules. These rapidly undergo chemical changes, producing free radicals that react with cellular components and lead to permanent damage.
As an immediate consequence of radiation damage, cells can undergo apoptosis, dying in interphase within a few hours of irradiation. Typical morphologic changes include loss of normal nuclear structure and degradation of DNA. DNA damage is important in triggering programmed cell death; membrane damage and signaling pathways are also thought to be involved.
A sufficiently high dose of radiation will inhibit mitosis. The inhibition of cellular proliferation is a primary mechanism by which radiation kills most cells. As radiation kills cells by inhibiting their ability to divide, its effects in living organisms occur primarily in tissues with high cell turnover or division rates, characterized by high proliferative activity. These include tissues such as the hone marrow and the mucosal lining of the stomach and small intestine. Another major target of radiation injury is the vascular system. Normal tissues experiences progressive and unremitting fibrosis, and occlusion of nutrient arteries and capillaries to soft tissues, following therapeutic radiation treatment for cancer. The secondary morbidity of this includes tissue necrosis and non-healing wounds.
The development of effective radioprotectant molecules is of great importance to populations potentially subjected to accidental, intentional or military exposure to radiation, including ionizing radiation.
In addition, the ability to prevent radiotherapy-induced toxicity without affecting antitumor therapeutic efficacy has the potential to enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects. Thus, another benefit to be realized from developing new cytoprotective therapies is to improve the therapeutic ratio by reducing the acute and chronic toxicities associated with more intensive and more effective anticancer therapies.